Project Summary Our broad, long-term goal is to develop rational therapeutics for the orphan disease pantothenate kinase- associated neurodegeneration (PKAN), an inborn error of vitamin B5 metabolism that is caused by defects in the gene that encodes PANK2, the first regulatory step in the coenzyme A biosynthetic pathway, and to do so as cost-effectively as possible. Children and adults affected by the disease develop a severe movement disorder and a characteristic pattern of abnormal iron accumulation in the brain. PKAN causes profound disability and suffering, especially in children, many of whom succumb to complications of the disease in the first decade of life. No proven disease-modifying therapy is currently available. In this project, we will build on recent work from the laboratory demonstrating a compelling, disease-relevant molecular and functional signature in the PKAN mouse brain that is recapitulated in both fibroblast cell cultures and in peripheral blood from human patients. This biological signature is ameliorated in vivo and in vitro by a product of intermediary metabolism in a dose-dependent fashion. In this application, we propose to extend this work to the clinic, evaluating the safety, tolerability and pharmacodynamic profile of the product in a phase 2, randomized, double-blind, placebo-controlled, dose- ranging, parallel-group study in children and adults with PKAN. A 6-month double-blind phase will be followed by an 18-month open-label phase. We will also explore the feasibility of applying a latent growth curve modeling approach to longitudinal natural history data to capture a disease modifying effect, with the goal of informing future study design. We will employ a novel approach to study conduct that is designed to reduce the barriers to study participation inherent in rare disease clinical research, minimize risks to subjects, and lessen the burden on families.